Liquisolid systems and methods of preparing same

ABSTRACT

A method of producing a free flowing and compressible liquid/power admixture of an active drug substance, by converting the active substance into a liquisolid system. This is accomplished by introducing by the drug into a non-volatile liquid or a mixture of non-volatile and volatile liquids to from a mixture, selecting at least one solid carrier material and admixing these components to produce a non-adherent, free-flowing and compressible liquid/power mass admixture, the amounts of drug and carrier being selected to optimize flow and compressibility.

This is a continuation of U.S. Ser. No. 09/136,035, filed Aug. 19, 1998and now U.S. Pat. Ser. No. 6,096,337, which is a continuation in part ofU.S. Ser. No. 08/937,240, filed Oct. 1, 1997 and now U.S. Pat. Ser. No.5,968,550, which is a divisional of U.S. Ser. No. 08/658,514, filed Jun.10, 1996 and now U.S. Pat. Ser. No. 5,800,834.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to powdered forms of liquid medicationsformulated to have both acceptable flow and acceptable compressioncharacteristics, and methods of producing them.

2. Description of the Related Art

It is well established that the active ingredient in a solid dosage formmust undergo dissolution before it is available for absorption from thegastrointestinal tract. The rate of absorption of a sparinglywater-soluble drug, formulated as an orally administered solid dosageform, is controlled by its dissolution rate in the fluid present at theabsorption site, i.e., the dissolution rate is often therate-determining step in drug absorption. Since they exhibit poor anderratic dissolution profiles, most water-insoluble drugs are included bythe FDA in the list of drugs having a high risk for therapeuticinequivalence due to differences and inconsistencies in bioavailability.

Various techniques have been employed to formulate drug delivery systemswhich would enhance the dissolution profile and, in turn, the absorptionefficiency of water-insoluble solid drugs such as digoxin, digitoxin,prednisolone, hydrocortisone, prednisone, spironolactone,hydrochlorothiazide, polythiazide, and/or liquid lipophilic medicationssuch as clofibrate, chlorpheniramine, water-insoluble vitamins, fishoil, etc. Drug micronization, solid dispersion, coprecipitation,lyophilization, microencapsulation and inclusion of drug solutions orliquid drugs into soft gelatin capsules or specially sealed hard shellcapsules are some of the major formulation tools which have been shownto enhance the dissolution characteristics of water-insoluble drugs.

Despite their high production cost and technologically demanding,patented and advanced preparations, soft gelatin capsules represent aunique approach for the formulation of liquid oily medications and/ordrug solutions of water-insoluble solid drugs. Comparing various digoxinoral solid dosage forms, Ebert (1) has reported that soft gelatincapsule products demonstrated the highest and most consistentbioavailability, mainly due to the fact that the drug is already insolution. Nelson, in his review (2), points out that the availability ofdrug for absorption from various types of oral formulations, usuallydecreases in the following order: solution, suspension, powdered-filledcapsule, compressed tablet, coated tablet.

A more recent technique, entitled “powdered solution technology”, hasbeen applied to prepare water-insoluble drugs into rapid release soliddosage forms. Powdered solutions are designed to contain liquidmedications in powdered form, thereby possessing mechanisms of drugdelivery similar to those of soft gelatin capsule preparationscontaining liquids. The concept of powdered solutions enables one toconvert drug solutions or liquid drugs into acceptably flowing powdersby a simple admixture with selected powder excipients (e.g., celluloseand silica). Several investigators (3-8) have used a similar approach toimprove the release profiles of several water-insoluble drugs.

However, the industrial application of this technique has been hamperedby the poor and erratic flowability and compressibility of the producedliquid/powder admixtures. Flow problems of such systems were addressedby the introduction of a new theoretical model for the principlesunderlying the formation of powdered solutions (3, 4). The developedmathematical expressions were shown to successfully allow forcalculation of the optimum amounts of ingredients required to produceliquid/powder admixtures possessing, to a pre-specified desirabledegree, acceptable flow characteristics.

In the same studies, a key concept termed flowable liquid-retentionpotential or Φ-value (phi) of a powder was introduced and defined as themaximum amount of liquid that the unit weight of a powder material canretain inside its bulk while at the same time maintaining acceptableflowability. Moreover, Φ-values of several powder excipients weredetermined using the “angle of slide” test to evaluate flow propertiesof liquid/powder admixtures containing light mineral oil as theincorporated liquid. The limit of acceptable flowability was set at anangle of slide equal to 33°. Criticism of that work was based on thefacts that the “angle of slide” test does not necessarily represent arealistic evaluation of flow characteristics and that liquids other thanlight mineral oil should have been also used to test the powders.

In subsequent projects (5), acceptably flowing tablet formulations ofclofibrate (liquid drug) and prednisolone (dissolved in a non-volatilesolvent system), made according to the new mathematical flowabilitymodel, displayed consistently good flow properties and significantlyhigher dissolution profiles than those of commercial products, includingsoft gelatin capsule preparations. However, while evaluating thedissolution profiles of liquisolid tablets of clofibrate,compressibility problems were revealed. Specifically, such liquisolidformulations of clofibrate could not be compressed into tablets ofsatisfactory hardness. While obtaining superior dissolution profiles ofsuch “soft” clofibrate liquisolid tablets as compared to those ofcommercial soft gelatin capsules, an apparent plateau of theirdissolution curves at the 80% level (cumulative percent of drug releasedversus time) was also observed. It has been concluded that thisphenomenon occurred due to respective amounts of liquid drug beingsqueezed out of the liquisolid tablet during compression. Hence, eventhough the flowability model and the Φ-value concept may ensureacceptable flow characteristics of liquisolid preparations, they havebeen proven inadequate to yield products possessing, to a pre-specifieddegree, acceptable compression properties.

For this reason, there is a need for a method of producing on anindustrial scale, acceptably flowing and, simultaneously, compressibleliquid/powder admixtures of liquid medications.

OBJECTS AND SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a methodof ensuring the consistent production of acceptably flowing andcompressible liquid/powder admixtures of liquid medications.

It is also an object of the present invention to provide a means ofoptimizing the amounts of excipients required to yield such free-flowingand compressible liquid/powder admixtures.

The present invention is thus directed to a method of converting aliquid medication into a liquisolid system, wherein the liquidmedication is incorporated into a specific amount of carrier material,and the resulting wet mixture is blended with a calculated amount ofcoating material to produce a “dry” (i.e. dry-looking), nonadherent,liquid/powder admixture which possesses acceptable flow and,simultaneously, acceptable compression characteristics.

A new formulation-mathematical model, which includes a redefinedfundamental flow property of powders termed flowable liquid-retentionpotential (Φ-value) and introduces a new fundamental compressionproperty of powders termed compressible liquid-retention potential(Ψ-number), is provided to calculate the optimum amounts of carrier andcoating materials required to yield such acceptably flowing andcompressible liquid/powder admixtures.

Furthermore, two new testing procedures termed the “LiquisolidFlowability Test” and the “Liquisolid Compressibility Test” which arerequired to assess the Φ-values and Ψ-numbers of powder excipients, areintroduced.

Finally, various representative immediate and sustained releaseliquisolid tablet formulations and their flowability and compressibilityevaluations and in-vivo and in-vivo release profiles compared tocommercial products are included.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic outline of steps involved in the preparation ofliquisolid systems.

FIG. 2 is a graph showing the comparative dissolution profiles ofprednisone from (1 mg and 5 mg)immediate-release liquisolid andcommercial tablets.

FIG. 3 is a graph showing the comparative dissolution profiles ofmethyclothiazide from (5 mg)immediate-release liquisolid and commercialtablets.

FIG. 4 is a graph showing the comparison of mean cumulative amounts ofclofibrate released from immediate-release 100 mg liquisolid tablets and500 mg commercial soft gelatin capsules.

FIG. 5 is a graph showing the comparative dissolution profiles of freshand 10-months old hydrocortisone liquisolid tablets.

FIG. 6 is a graph showing clofibrate plasma levels in rats over a periodof three hours for formulations comprising 10 mg/kg of liquisolidcompacts or commercial Atromid-S soft gelatin capsules.

FIG. 7 is a graph showing gemfibrozil plasma levels in rats over aperiod of six hours after oral administration (10 mg/kg) of aimmediate-release liquisolid compact formulation and commercial Lopid600 mg tablets.

FIG. 8 is a graph showing nifedipine plasma levels in rats over a periodof twelve hours after oral administration (0.1 mg/kg) ofimmediate-release liquisolid compact formulation and commercial softgelatin capsules.

FIG. 9 is a graph showing the comparative dissolution profiles ofnifedipine from (30 mg) sustained release liquisolid and commercialtablets.

DEFINITIONS

As used herein, the following terms have the meaning described belowunless otherwise indicated:

The term “liquid medication” includes liquid lipophilic drugs and drugsuspensions or solutions of solid water-insoluble drugs in suitablenon-volatile solvent systems.

The term “water-insoluble drugs” includes those drugs that are“sparingly water-soluble” (1 part solute into 30 to 100 parts of water),“slightly water-soluble” (1 part solute into 100 to 1000 parts ofwater), “very slightly water-soluble” (1 part solute into 1000 to 10,000parts of water), and “practically water-insoluble” or “insoluble” (1part solute into 10,000 or more parts of water), as defined in USP XXIIor Remington's Pharmaceutical Sciences.

The term “liquisolid systems” refers to powdered forms of liquidmedications formulated by converting liquid lipophilic drugs, or drugsuspensions or solutions of water-insoluble solid drugs in suitablenon-volatile solvent systems, into “dry” (i.e., dry-looking),nonadherent, free-flowing and readily compressible powder admixtures byblending with selected carrier and coating materials. Based on the typeof liquid medication contained therein, liquisolid systems may beclassified into three subgroups: “powdered drug solutions,” “powdereddrug suspensions,” and “powdered liquid drugs.” The first two may beproduced from the conversion of drug solutions (e.g., prednisolonesolution in propylene glycol) or drug suspensions (e.g., gemfibrozilsuspension in Polysorbate 80), and the latter from the formulation ofliquid drugs (e.g., clofibrate, valproic acid, liquid vitamins, etc.),into liquisolid systems.

The term “liquisolid compacts” refers to immediate or sustained releasetablets or capsules that are prepared using the technique describedunder “liquisolid systems,” combined with the inclusion of appropriateadjuvants required for tabletting or encapsulation, such as lubricants,and for rapid or sustained release action, such as disintegrants orbinders, respectively.

The term “liquisolid Microsystems” refers to capsules prepared by thetechnique described under “liquisolid systems” combined with theinclusion of an additive, e.g., polyvinylpyrrolidone (PVP), in theliquid medication wherein the resulting unit size may be as much as fivetimes less than that of liquisolid compacts.

The term “flowable liquid-retential potential” (Φ-value) of a powdermaterial describes its ability to retain a specific amount of liquidwhile maintaining good flow properties. The Φ-value is defined as themaximum weight of liquid that can be retained per unit weight of thepowder material in order to produce an acceptably flowing liquid/powderadmixture.

The term “compressible liquid-retential potential” (Ψ-number) of apowder material describes its ability to retain a specific amount ofliquid while maintaining good compression properties. The Ψ-number isdefined as the maximum weight of liquid that can be retained per unitweight of the powder material in order to produce an acceptablycompressible liquid/powder admixture, i.e., being able to yield tabletsof satisfactory mechanical crushing strength (hardness) withoutpresenting any liquid squeezing out of the liquisolid mass duringcompaction.

The term “pactisity” (Ω) of a liquisolid system is the maximum crushingstrength (hardness) of a one-gram tablet of the system compressed atstandard pactisity conditions (SPC).

The term “plateau compressional force” is the force required to achievemaximum powder cohesiveness which, in turn, results in maximum tablethardness.

The term “carrier material” refers to a preferably porous materialpossessing sufficient absorption properties, such as microcrystallineand amorphous cellulose, which contributes in liquid absorption.

The term “coating material” refers to a material possessing fine andhighly adsorptive particles, such as various types of amorphous silicondioxide (silica), which contributes in covering the wet carrierparticles and displaying a dry-looking powder by adsorbing any excessliquid. These adsorptive particles have a particle size range of about10 nm to 5,000 nm in diameter.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENT

Liquisolid systems are acceptably flowing and compressible powderedforms of liquid medications. A schematic outline of steps involved inthe preparation of liquisolid systems is provided in FIG. 1. As seenthere, a liquid lipophilic drug (e.g., chlorpheniramine, clofibrate,valproic acid, water-insoluble vitamins, fish oil, etc.) can beconverted into a liquisolid system without being further modified. Onthe other hand, if a solid water-insoluble drug (e.g., gemfibrozil,nifedipine, digoxin, digitoxin, polythiazide, hydrochlorothiazide,methyclothiazide, etoposide, spironolactone, prednisolone, prednisone,hydrocortisone, etc.) is formulated, it should be initially dissolved orsuspended in a suitable-non-volatile solvent system to produce a drugsolution or drug suspension of desired concentration. Inert, highboiling point, preferably water-miscible and not highly viscous organicsolvent systems (e.g., propylene glycol, liquid polyethylene glycols,polysorbates, glycerin, N,N-dimethylacetamide, fixed oils, etc.) aremost suitable for this process.

Next, a certain amount of the prepared drug solution or suspension, orthe liquid drug itself, is incorporated into a specific quantity ofcarrier-material which should be preferably of a porous nature andpossessing sufficient absorption properties. Materials with a poroussurface and closely matted fibers in their interior, such as powder andgranular grades of microcrystalline and amorphous cellulose, are mostpreferred as carriers. The resulting wet mixture is then converted intoa dry-looking, nonadherent, free-flowing and readily compressible powderby the simple addition and mixing of a calculated amount of coatingmaterial. Excipients possessing fine and highly adsorptive particles,such as various types of amorphous silicon dioxide (silica), are mostsuitable for this step. Before compression or encapsulation, variousadjuvants such as lubricants and disintegrants (immediate-release) orbinders (sustained-release) may be mixed with the finished liquisolidsystems to produce liquisolid compacts (tablets or capsules).

Based on the type of liquid medication contained therein, liquisolidsystems may be classified into three subgroups: “powdered drugsolutions,” “powdered drug suspensions” and “powdered liquid drugs.” Thefirst two may be produced from the conversion of drug solutions or drugsuspensions and the latter from the formulation of liquid drugs intoliquisolid systems.

Based on the formulation technique used, liquisolid systems may beclassified into two categories, namely, liquisolid compacts orliquisolid microsystems. The first are prepared using the previouslyoutlined method to produce tablets or capsules, whereas the latter arebased on a new concept which employs similar methodology combined withthe inclusion of an additive, e.g., polyvinylpyrrolidone (PVP), in theliquid medication which is incorporated into the carrier and coatingmaterials to produce an acceptably flowing admixture for encapsulation.The advantage stemming from this new technique is that the resultingunit size of liquisolid microsystems may be as much as five times lessthan that of liquisolid compacts.

Regarding “powdered drug solutions,” it must be emphasized that theirpreparation is not a solvent deposition technique since it does notinvolve drying or evaporation. Since non-volatile solvents are used toprepare the drug solution or suspension, the liquid vehicle does notevaporate and thus, the drug is carried within the liquid system whichin turn, is dispersed throughout the final product.

The production of liquisolid systems possessing acceptable flowabilityand compressibility has been addressed with the development of a newformulation-mathematical model, based on the new fundamental powderproperties termed “flowable (Φ-value) and compressible (Ψ-number) liquidretention potentials” of the constituent powders. According to theproposed theories, the carrier and coating materials can retain onlycertain amounts of liquid while maintaining acceptable flow andcompression properties. Depending on the excipient or carrier: coatingratio (R) of the powder system used, which is the ratio between thequantities of carrier (Q) and coating (q) materials present in theformulation (R=Q/q), there is a characteristic maximum liquid load onthe carrier material, termed “load factor” (L_(f)) and defined as theratio of the amount of liquid medication (W) over the quantity ofcarrier material (Q) in the system (L_(f)=W/Q), which should bepossessed by an acceptably flowing and compressible liquisolid system.

The two key properties of liquisolid powder excipients, namely, Φ-valueand Ψ-number, may be determined by two recently developed methods,termed “liquisolid flowability (LSF) and liquisolid compressibility(LSC) tests.” In the LSF test, recording powder flowmetry is employed toassess and classify powder flow characteristics such as flow rate andconsistency, whereas in the LSC test, a newly introduced powdercompaction property termed “pactisity”, Ω, and the derived linear“pactisity equation” are used to classify compression characteristics ofprepared liquisolid systems.

1. If a solid water-insoluble drug is formulated, the drug is firstdissolved or suspended in a non-volatile solvent (e.g., propyleneglycol, polyethylene glycol 400, glycerin, polysorbate 80, sorbitanmonolaurate, N,N, dimethylacetamide, fixed oils, other liquidsurfactants, etc.) to produce a drug solution or drug suspension ofcertain composition (% w/w concentration).

2. The weight W (in grams) of drug solution or suspension or liquid drugrequired to be included in a single liquisolid compact unit possessing adesired strength of active ingredient is selected.

3. The carrier (e.g., cellulose) and coating (e.g., silica) materials tobe included in the liquisolid formulation are selected.

4. The characteristic excipient or carrier:coating ratio R_(min) (w/w)and the flowable liquid-retention potentials (Φ-values, w/w) of thecarrier (Φ) and coating (φ) materials are determined using the“Liquisolid Flowability (LSF) Test” as summarized below.

5. The compressible liquid-retention potentials (Ψ-numbers, w/w) of thecarrier (Ψ) and coating (ψ) materials are determined using the“Liquisolid Compressibility (LSC) Test” as summarized below.

6. The desired excipient or carrier:coating ratio R, where R>R_(min), ofthe carrier:coating combination to be included in the liquisolid systemis selected. If minimum unit dose weight (U_(min)) is desired, theexcipient ratio of the formulation must be selected to be equal toR_(min) which is the characteristic minimum excipient ratio of thecarrier:coating system used.

7. The optimum load factor L_(o) (w/w) required to yield an acceptablyflowing and compressible liquisolid system is assessed using Equations1-4.

L _(o) =ΦL _(f) when ΦL _(f) <ΦL _(f)  (Eq. 1)

or

L _(o) =ΨL _(f) when ΦL _(f) >ΨL _(f)  (Eq. 2)

where:

ΦL _(f)=Φ+φ(1/R)  (Eq. 3)

and

ΨL _(f)=Ψ+ψ(1/R)  (Eq. 4)

If a powder system (carrier:coating) mixed at its minimum excipientratio (R_(min)) has been selected, the required maximum load factor Lomay be determined using Equations 5-8.

L _(max) =ΦL _(max) when ΦL _(max) <ΨL _(max)  (Eq. 5)

or

L _(max) =ΨL _(max) when ΦL _(max) >ΨL _(max)  (Eq. 6)

where:

ΦL _(max)=Φ+φ(1/R _(min))  (Eq. 7)

and

ΨL _(max)=Ψ+ψ(1/R _(min))  (Eq. 8)

8. Finally, the optimum quantities (in grams) of carrier (Q_(o)) andcoating (q_(o)) materials required to be mixed with the desired amount Wof liquid in order to produce an acceptably flowing and compressibleliquisolid compact are determined using Equations 9 and 10,respectively.

Q _(o) =W/L _(o)  (Eq. 9)

q _(o) =Q _(o) /R  (Eq. 10)

The minimum carrier quantity (Q_(min)) and maximum coating quantity(q_(max)) required to produce an acceptably flowing and compressibleliquisolid compact unit possessing minimum weight (U_(min)) andcontaining an amount W of liquid may be assessed using Equations 11 and12, respectively.

Q _(min) =W/L _(mix)  (Eq. 11)

q _(max) =Q _(min) /R _(min)  (Eq. 12)

It must be pointed out that, in terms of producing compacts of realisticunit size, the practical substance of the liquisolid formulation desiredto be prepared may be assessed by predicting its unit dose weight U_(w)using Equation 13. This can be done as long as the weight W of theliquid medication (to be included in a single liquisolid compact unit)and the desired excipient ratio R of the formulation have been selectedleading to the determination of the required optimum load factor L_(o).The minimum possible unit dose weight U_(min) which can be produced bythe carrier:coating system may be also predicted using Equation 14,having selected the weight W of the liquid medication (per unit dose)and having determined the minimum excipient ratio R_(min) of the powdersystem and its corresponding maximum load factor L_(max) required toyield a flowable and compressible liquisolid system.

U _(w) =W+W (1+1/R)(1/L _(o))  (Eq. 13)

U _(min) =W+W (1+1/R _(min))(1/L _(max))  (Eq. 14)

The formulation steps and mathematical expressions employed to calculatethe optimum amounts of carrier and coating materials to produceacceptably flowing and compressible liquisolid systems have beencompiled in Table 1.

Liguisolid Flowability (LSF) Test

A test method, called the liquisolid flowability NSF) test, wasdeveloped and employed to determine the flowable liquid retentionpotential (Φ-value) of several powder excipients likely to be includedin liquisolid compacts. The test is basically a titration-like procedurein which 25 to 30 grams of mixtures of the powders under investigation,with increasing amounts of a non-volatile solvent (i.e., liquid/solidweight composition), such as, for example, propylene glycol,polyethylene glycol, light mineral oil and clofibrate, are preparedusing a standard mixing process which ensures uniformity, and their flowrate and consistency are assessed using a recording powder flowmeter(RPF). The liquid/solid weight composition (w/w) in that admixture whichjust complies with a desired and pre-selected limit of acceptableflowability, is taken as the Φ-value of the excipient. Accordingly, theliquid/powder admixture with liquid content slightly higher than theΦ-value of the powder material should not be flowing within the desiredlimit of acceptable flow. It should be noted that the non-volatilesolvent used in the LSF test should be the one selected to be includedin the liquid medication (drug solution or drug suspension) of thetargeted liquisolid product; where a liquid drug is formulated, then theLSF test should be conducted with the liquid drug itself.

Basically, the method consists of the following steps:

a. Preparing several powder systems each containing a carrier materialand a coating material and selecting for each system a carrier:coatingratio, R_(1 . . . x),

where _(1 . . . x) corresponds to the powder systems prepared,

R_(1 . . . x)=Q_(1 . . . x)/q_(1 . . . x),

Q_(1 . . . x)=the weight of the carrier material, and

q_(1 . . . x)=the weight of the coating material,

such that, R₁=Q₁/q₁, R₂=Q₂/q₂, R₃=Q₃/q₃ . . . R_(x)=Q_(x)/q_(x);

b. Preparing several uniform liquid/powder admixtures of differentliquid/solid weight compositions (C_(w)) by combining one of the powdersystems prepared in step (a) with increasing amounts of a non-volatilesolvent, wherein the non-volatile solvent is selected from that which isto be included in the liquid medication (drug solution, drugsuspension), or the liquid drug itself, of the targeted liquisolidproduct;

C. Assessing the flow rate and consistency of the admix thus obtainedusing a recording powder flowmeter and determining from this assessmentthe flowable liquid load factor (^(Φ)L_(f)) of the powder system whichcomplies with a preselected limit of acceptable flowability, where^(Φ)L_(f)=W/Q, W=the weight of the liquid and Q=the weight of thecarrier material;

d. Repeating steps (b) and (c) for the remaining powder systems of step(a) to determine the flowable liquid load factors of these systems; and

e. Plotting the flowable liquid load factors (^(Φ)L_(f)) thus obtainedagainst the corresponding reciprocal carrier:coating ratios (1/R) of thepowder systems, thereby obtaining a linear plot having a Y-interceptequal to the flowable liquid-retention potential (Φ-value) of thecarrier material (Φ) and a slope equal to the flowable liquid-retentionpotential (Φ-value) of the coating material (φ).

The LSF test can be used not only for the preparation of acceptablyflowing liquisolid compacts, but also for the general evaluation of theflowability of powders.

Limit of Acceptable Flowability

In the present studies, a powder, or a liquid/powder admixture, wasconsidered as possessing acceptable flow properties, if 25 to 30 gramsof the liquid/powder sample was able to pass through the hopper of theRPF assembly (at a vibration level produced by a standard pressure of 10psi) exhibiting a flow rate not less than 4 gram/sec and flowconsistency without any blockages at the start or during the powderflow. Since the objective of these studies was to investigate theΦ-value concept in a comparative fashion, the line of acceptable flowwas drawn in a more or less arbitrary manner. The above conditions werechosen based on results of preliminary work indicating that the powderflow of model formulations was satisfactory on a Zanasi LZ-64 capsulemachine (Zanasi Co., Bologna, Italy). When selecting another machine,however, the limits of acceptable flowability should be calibrated andadjusted to the requirements of that specific piece of equipment.Consequently, by altering the limits of acceptable flow, the samepowders might display different Φ-values.

Liquisolid Compressibility (LSC) Test

A test method, called the liquisolid compressibility (LSC) test, wasdeveloped and employed to determine the compressible liquid-retentionpotential, i.e., Ψ-number, of several powder excipients likely to beincluded, as carrier or coating materials, in liquisolid compacts.Basically, the method consists of the following steps:

a. Preparing several powder systems each containing a carrier materialand a coating material and selecting for each system a carrier:coatingratio, R_(1 . . . x).

where _(1 . . . . x) corresponds to the powder systems prepared,

R_(1 . . . x)=Q_(1 . . . x)/q_(1 . . . x),

Q_(1 . . . x)=the weight of the carrier material, and

q_(1 . . . x)=the weight of the coating material,

such that, R₁=Q₁/q₁, R₂=Q₂/q₂, R₃=Q₃/q₃ . . . R_(x)=Q_(x)/q_(x);

b. Preparing several uniform liquid/powder admixtures of differentliquid/solid weight compositions (C_(w)) by combining one of the powdersystems prepared in step (a) with increasing amounts of a non-volatilesolvent, wherein the non-volatile solvent is selected from that which isto be included in the liquid medication (drug solution, drugsuspension), or the liquid drug itself, of the targeted liquisolidproduct;

c. Compressing each liquid/powder admixture thus obtained into tabletsof certain weight using plateau compressional force to achieve maximumtablet crushing strength;

d. Assessing the average tablet crushing strength, S_(c), of the tabletsproduced and calculating their pactisity, Ω, where Ω=S_(c)/W_(t) andW_(t)=the average tablet weight in grams;

e. Determining the average liquid content of the crushed tablets andcalculating the net liquid/solid weight composition (C_(w)) of thecrushed liquid/powder admixture;

f. Determining the characteristic intrinsic pactisity, Ω_(o), and spongeindex, σ_(i), of the powder system by plotting the data obtained as logΩ versus C_(w). where log Ω=log Ω_(o)−σ_(i)·C_(w);

g. Determining the Ψ_(min) which is the compressible liquid retentionpotential (Ψ-number) of the powder system, where

Ψ_(mix)=(log Ω_(o)−log 20)/σ_(i);

h. Determining the compressible liquid-load factor (^(Ψ)L_(f)) of thepowder system, where ^(ΨL) _(f)=Ψ_(mix) (1+1/R);

i. Repeating steps (b) through (h) for the remaining powder systems ofstep (a) to determine their compressible liquid load factors; and

j. Plotting the compressible liquid load factors thus obtained againstthe corresponding reciprocal carrier:coating ratios (1/R) of the powdersystems, thereby obtaining a linear plot having a Y-intercept equal tothe compressible liquid-retention potential (Ψ-number) of the carriermaterial (Ψ) and a slope equal to the compressible liquid-retentionpotential (Ψ-number) of the coating material ψ

Therefore, the Ψ-number of a powder represents a certain liquid/solidcontent (w/w) C_(w) that when compressed at plateau pressures, termedstandard pactisity conditions, will yield a compact possessing apactisity Ω equal to 20 kg/g.

The LSC test can be used not only for the preparation of acceptablycompressible liquisolid compacts, but also for the general evaluation ofthe compactibility of powder excipients and formulations Compared tocurrent methods of “compaction simulation,” the LSC test is simple,accurate and reproducible.

TABLE 1 Formulation and Mathematical Model of Liquisolid Systems OptimumCarrier and Formulation Steps Optimum Load Factor Lo Coating QuantitiesSelection of the weight (W) of Lo = ^(φ)Lt when ^(Φ)Lt < ^(Ψ)lt Qo =W/Lo drug solution or liquid drug or and Selection of the carrier and Lo= ^(ψ)Lt when ^(Φ)Lt > ^(Ψ)lt qo = Qo/R coating powder materialsDetermination of Φ-value, Ψ-number and R_(min) of powders Selection ofdesired excipient where: Prediction of Unit ratio (R) of thecarrier:coating ^(φ)Lt = Φ + φ (1/R) Dose Weight (Uw) powder system (R >R_(min)) and Uw = W + W(1 + 1/R)(1/Lo) Determination of the optimum^(Ψ)Lt = Ψ + ψ (1/R) load factor (Lo) of formulation Determination ofthe optimum quantities of carrier (Qo) and coating (qo) materialsSymbolism: W, Qo and qo: optimum quantities of liquid, carrier andcoating materials, respectively. Φ and φ: flowable liquid retentionpotential (Φ-value) of carrier and coating material. Ψ and ψ:compressible liquid retention potential (Ψ-number) of carrier andcoating material.

Determined physical properties of powder excipients, i.e., Φ-value,Ψ-number and R_(min), essential to the formulation of flowable andcompressible liquisolid compacts, and determined by the previouslydescribed LSF and LCS testing, are compiled in Table 2.

TABLE 2 Liquid Formulation Parameters of Various Powder ExcipientsLiquidsolid Formulation Parameters^(a) Minimum Powder ExcipientsExcipient Φ-value (w/w) Ψ-value (w/w) or Systems Ratio R_(min) PG PEG400 CLF PG PEG 400 CLF Avicel PH 102 0.16 0.005 0.00 0.224 0.242 0.086Avicel PH 200 0.26 0.02 0.01 0.209 0.232 0.046 E.G.C. 0.25 — — 0.227 — —Cab-O-Sil M5 (silica)^(b) 18 3.31 3.26 1.68 0.560 0.653 1.554 withAvicel PH 102 Ca-O-Sil M5 (silica)^(b) 8 2.57 2.44 1.83 0.712 0.7171.709 with Avicel PH 200 Ca-O-Sil M5 (silica)^(b) 7 3.44 — — 0.881 — —with E.G.C. Syloid 244 FP (silica)^(b) 7 2.63 — — 0.797 — — with AvicelPH 200 ^(a)Φ-values, Ψ-numbers and R_(min) determined using LSF, LSC andB-LSC tests (see chapters 2 & 3) ^(b)Included as the coating material incarrier:coating powder systems; the carrier is written in italics.

Advantages of Liquisolid Systems

A great number of slightly and very slightly water-soluble andpractically water-insoluble liquid and solid drugs, such as thosepreviously mentioned, can be formulated into liquisolid systems usingthe new formulation-mathematical model. It is well established thatbetter availability of an orally administered water-insoluble drug isachieved when the drug is in solution form. That is why soft gelatincapsules containing solubilized forms of such medications demonstratehigher bioavailability compared to conventional oral solid dosage forms.The same principle governs the mechanism of drug delivery fromliquisolid systems, specifically, powdered drug solutions, and ischiefly responsible for the improved dissolution profiles exhibited bythese preparations. In this instance, even though the drug is in atabletted or encapsulated dosage form, it is held in a solubilizedliquid state, which consequently contributes to increased drug wettingproperties, thereby enhancing drug dissolution.

Another advantage of liquisolid systems is that their production cost islower than that of soft gelatin capsules because the production ofliquisolid systems is similar to that of conventional tablets. Stillanother possible advantage of liquisolid systems, particularly forpowdered liquid drugs, should be mentioned. During dissolution of aliquisolid tablet, after the disintegration process is completed, thedrug solution or liquid drug, carried on the suspended and thoroughlyagitated primary particles, is dispersed throughout the volume of thedissolution medium; such a phenomenon does not extensively occur duringthe dissolution process of soft gelatin capsule preparations. Therefore,since more drug surface is exposed to the dissolving medium, liquisolidsystems exhibit enhanced drug release.

Most liquid or solid “water-insoluble drugs” may be formulated intoimmediate-release or sustained-release “liquisolid compacts” or“liquisolid Microsystems.”

Optimized rapid-release liquisolid tablets or capsules ofwater-insoluble drugs exhibit enhanced in-vitro and in-vivo drug releaseas compared to their commercial counterparts, including soft gelatincapsule preparations, as illustrated in FIGS. 2-8.

Optimized sustained-release liquisolid tablets or capsules ofwater-insoluble drugs exhibit surprisingly constant dissolution rates(zero-order release) comparable only to expensive commercialpreparations that combine osmotic pump technology and laser-drilledtablets, as illustrated in FIG. 9.

Testing of the Invention

Liquisolid tablet formulations of the oily liquid drug, clofibrate, andof several water-insoluble solid drugs such as nifedipine, gemfibrozil,hydrocortisone, prednisolone, prednisone, spironolactone,methylclothiazide, and hydrochlorothiazide dissolved in suitablenon-volatile solvents, were evaluated. Additionally, the in-vitrodissolution profiles of such liquisolid products were compared withthose of their commercial counterparts. Furthermore, the effects ofaging on the crushing strengths and dissolution profiles of preparedliquisolid tablets were also investigated. Finally, in-vivo studies wereconducted in rats to compare clofibrate, nifedipine and gemfibrozilliquisolid compacts with their commercial counterparts.

Materials

The following materials were used as received: gembibrozil (Sigma Chem.Corp., St. Louis, Mo.); nifedipine (Barr Laboratories, Inc., Pomona,N.Y.); hydrochlorothiazide USP and hydrocortisone USP (Ciba-Geigy Co.,Pharmaceuticals Division, Summit, N.J.); spironolactone USP,prednisolone USP and methyclothiazide USP (Geneva Pharmaceuticals, Inc.,Broomfield, Colo.); prednisone USP (Amend, Drug & Chemical Co.,Irvington, N.J.); clofibrate (Ayerst Laboratories, Inc., New York,N.Y.); propylene glycol (Sigma Chemical Co., St. Louis, Mo.);polyethylene glycol 400 and polysorbate 80 (Tween® 80) (Ruger ChemicalCo., Inc., Irvington, N.J.); microcrystalline celluloses, i.e., Avicel®PH 102-granular MCC grade and Avicel® PH 200coarse granular MCC grade(F.M.C. Corp., Princeton, N.J.); experimental grade of granularamorphous cellulose (E.G.C.) sodium starch glycolate (Explotab®) (EdwardMendell Co., Inc., Carmel, N.Y.); amorphous silicon dioxides, i.e.,Cab-O-Sil® M5 (Cabot Corp., Tuscola, Ill.) and Syloid® 244 FP (C. W.Grace Co., Davison Chemical Division, Baltimore, Md.);hydroxypropylmethylcellulose (HPMC) with viscosity grade 15 cps(Shin-etsu Chemical Co., Tokyo, Japan); and polyvinylpyrrolidone (PVP)(ISP Chemical Co., Bound Brook, N.J.).

The following commercially available products were used for the purposeof drug dissolution profile comparisons with liquisolid tabletformulations: Hydrocortone® 10 mg hydrocortisone, MSD tablets (Merck,Sharp & Dohme, West Point, Pa.) prednisolone 5 mg tablets, USP (Rugbylaboratories, Rockville Centre, LI, N.Y.), Meticorten® 1 mg prednisonetablets, USP (Schering Corp., Kenilworth, N.J.), Deltasone® 5 mgprednisone tablets, USP (Upjohn Co., Kalamazoo, Minn.), Aldactone® 25 mgspironolactone tablets, USP (G. D. Searle & Co., Chicago, Ill.),Esidrix® 25 mg hydrochlorothiazide tablets, USP (Ciba-Geigy Co.,Pharmaceuticals Division, Summit, N.J.), methyclothiazide 5 mg tablets,USP (Geneva Generics, Broomfield, CO), Atromid-S® 500 mg clofibrate softgelatin capsules (Ayerst Laboratories, Inc., New York, N.Y.), Lopid 600mg gemfibrozil tablets (Parke-Davis, Div. of Warner Lambert Co., MorrisPlains, N.J.) and nifedipine 10 mg soft gelatin capsules (BlockPharmaceuticals, Newark, N.J.).

Major pharmacological and physicochemical properties (10) of the activeingredients used are briefly discussed below:

1. Hydrocordsone, the principal natural glucocorticoid in man, is awhite to practically white, odorless, crystalline powder which melts atabout 215° C., with some decomposition. It is very slightly soluble inwater and ether, slightly soluble in chloroform; 1 gram of drug issoluble in 40 ml of alcohol.

2. Prednisolone, a glucocorticoid 4 times more potent thanhydrocortisone, is a white to practically white, odorless, crystallinepowder which melts at about 235° C., with some decomposition. It is veryslightly soluble in water; 1 gram of drug is soluble in 30 ml of alcoholand in 180 ml of chloroform.

3. Prednisone, a glucocorticoid 3 to 5 times more potent thanhydrocortisone, is a white to practically white, odorless, crystallinepowder which melts at about 230° C., with some decomposition. It is veryslightly soluble in water; 1 gram of drug is soluble in 150 ml ofalcohol and in 200 ml of chloroform.

4. Spironolactone, a steroid acting as a competitive antagonist ofaldosterone, is a light cream-colored to light tan crystalline powderwith faint to mild mercaptan-like odor. It is practically insoluble inwater, freely soluble in chloroform, soluble in alcohol and slightlysoluble in fixed oils. It melts between 198° C. and 207° C. withdecomposition.

5. Methyclothiazide, an orally effective diuretic and antihypertensiveagent of the thiazide group, is a white to practically white crystallinepowder which melts with decomposition at 220° C. It is tasteless andodorless or has a slight odor, and possesses a pk_(a)=9.4. It is freelysoluble in acetone; 1 gram of drug is soluble in more than 10,000 ml ofwater, in 92.5 ml of alcohol, in more than 10,000 ml of chloroform andin 2,700 ml of ether.

6. Hydrochlorothiazide, an effective diuretic 10 times more potent thanthe prototype benzothiadiazine diuretic, chlorothiazide, is a white topractically white, odorless crystalline powder which melts at about 268°C. with decomposition. It displays a pK_(a1)=7.9 and a pk_(a2)=8.6. Itis slightly soluble in water, freely soluble in sodium hydroxidesolution and in dimethylformamide, sparingly soluble in methanol, andinsoluble in ether and chloroform.

7. Clofibrate, an antilipidemic agent which significantly decreases theVLDL levels in persons with hypertriglyceridemia, is a stable, colorlessto pale yellow liquid with a faint odor and characteristic taste. It hasa boiling and decomposition point of 158-160° C. It is insoluble inwater and soluble in alcohol, chloroform and other common organicsolvents.

8. Gemflbrozil, an antilipidemic agent which is the drug of choice inthe treatment of hypertriglyceridemia, consists of white crystalsmelting at about 61°. It has a very low aqueous solubility and isclassified as a practically water-insoluble substance.

9. Nifedipine, a potent peripheral vasodilator, consists of yellowcrystals melting at 174° C. It is practically water-insoluble, slightlysoluble in alcohol and very soluble in acetone and chloroform. Specialcare should be taken during handling since nifedipine solutions areextremely light sensitive.

Methods A. Preparation of Liquisolid Tablet Formulations

Liquisolid tablet formulations of hydrocortisone, prednisolone,prednisone, spironolactone, methyclothiazide, hydrochlorothiazide andclofibrate were prepared using various cellulosic carriers (i.e.,Avicel® PH 102 and PH 200, and E.G.C.) and silica coating materials(i.e., Cab-O-Sil® M5 and Syloid® FP). For “powdered drug solutions” or“powdered drug suspensions” (i.e., liquisolid compacts of solid drugs),non-volatile solvents, such as, for example, propylene glycol (PG),polyethylene glycol 400 (PEG) and polysorbate 80, were employed toprepare the incorporated drug solutions or suspensions having, in someinstances, different drug concentrations (% w/w). The new mathematicalmodel was used to calculate the optimum quantities of ingredientsrequired (per unit dose) to yield acceptably flowing and compressiblesystems. Various amounts, ranging from 5% to 12% w/w, of thedisintegrant sodium starch glycolate (Explotab®) were included in allformulations in order to produce immediate-release preparations. Thefinished liquid/powder admixtures were compressed into cylindricaltablets possessing a specific crushing strength equal to 15 kg/g.

Preparation of Drug Solutions and Suspensions

For liquisolid compacts of solid drugs, non-volatile solvents (such asPG, PEG 400 and polysorbate 80) were employed to prepare the drugsolutions or suspensions having, in some instances, different drugconcentrations (% w/w). The desired quantities of solid drug andselected solvent were accurately weighed in a 20 ml glass beaker andthen heated to 80° C.-90° C. with constant stirring, until a homogeneousdrug solution was obtained. Selected amounts (W) of the resulting hotliquid medications were incorporated into calculated quantities ofcarrier and coating materials.

Mixing Process

A standard mixing process was used for all preparations. Initially, thecalculated ingredient quantities per unit dose, multiplied by a factorequal to 50 (to prepare 50-tablet batches), were accurately weighed in aplastic weighing boat. Then, the liquid-powder contents, weighing 25 to35 grams, were blended in a porcelain mortar with the aid of a pestleavoiding excessive trituration and particle size reduction. The mixingprocedure was conducted in three stages. During the first stage, thesystem was blended at an approximate mixing rate of one rotation persecond for approximately one minute in order to evenly distribute theliquid medication into the powder. In the second mixing stage, theliquid/powder admixture was evenly spread as a uniform layer on thesurfaces of the mortar and left standing for approximately five minutesto allow the drug solution or liquid drug to be absorbed in the interiorof the powder particles. In the third stage, the powder was scraped offthe mortar surfaces by means of an aluminum spatula, and then blendedwith a calculated quantity (5% to 12% w/w) of the disintegrant,Explotab®, for another thirty seconds, in a manner similar to the oneused in the first stage, producing the final liquisolid formulation tobe compressed.

Compression Process

The prepared liquisolid systems were manually compressed intocylindrical tablets of desired weight using a model B hydraulic CarverLaboratory Press (Fred S. Carver, Inc., Hydraulic Equipment, Summit,N.J.). Round, flat-face punches and die units possessing diametersvarying, according to intended tablet size, from {fraction (11/32)}″ to{fraction (16/32)}″ were used. All formulations were compressed intotablets possessing similar specific crushing strength, i.e., 15 kg/g.Specific crushing strength of a tablet is the ratio of its crushingstrength S_(c) (hardness) over its weight W_(t), i.e., S_(c)/W_(t). Forinstance, liquisolid tablets weighing 0.6 and 0.3 grams were compressedto a hardness (S_(c)) of 9 kg (i.e., 15 kg/g×0.6 g) and 4.5 kg (i.e., 15kg/g×0.3 g), respectively.

B. Examples of Prepared Liquisolid Tablet Formulations Hydrocorisone 5and 10 mg Liquisolid Tablets (HSN)

Four liquisolid tablet formulations of hydrocortisone, denoted as HSN-1,HSN-2, HSN-3 and HSN4, were prepared. Formulation HSN-1 contained 5 mgof hydrocortisone (per tablet) in the form of 0.15 g of its 3.33% w/wsolution in PG, mixed with an E. G. C. Cab-O-Sil® M5 system possessingan excipient ratio equal to 10. Formulations HSN-1 and HSN-2 contained10 mg of hydrocortisone (per tablet) in the forms of 0. 15 g of its6.66% w/w solution and 0.1 g of its 10% w/w solution in PG,respectively. In both preparations, an Avicel® PH 200:Cab-O-Sil® M5powder system was included at an excipient ratio equal to 10. Finally,formulation HSN4 contained 10 mg of hydrocortisone (per tablet) in theform of 0.1 g of its 10% w/w solution in PG, mixed with an Avicel® PH102:Cab-O-Sil® M5 powder combination possessing excipient ratio equal to20. A 12% w/w of the disintegrant Explotab® was included in allliquisolid compacts. The prepared hydrocortisone tablet formulations arelisted in Table 3.

Prednisolone 5 mg Lquisold Tablets (PLN)

Four liqlisolid tablet formulations of prednisolone, denoted as PLN-1,PLN-2, PLN-3 and PLN4, were prepared. All systems contained 5 mg ofprednisolone (per tablet) in the form of 0.108 g of its 4.63% w/wsolution in PG, and various carrier:coating combinations. Specifically,the powder systems Avicel® PH 102:Cab-O-Sil® M5(at R=R_(min)=18),Avicel® PH 200:Cab-O-Sil® M5 (R_(min)=8), Avicel® PH 200:Syloid® 244 FP(R_(min)=7) and E. G. C. :Cab-O-Sil® M5 (R_(min)=7) were included attheir minimum excipient ratios in formulations PLN-1, PLN-2, PLN-3 andPLN4, respectively. A 12% w/w of Explotab® was included in allliquisolid compacts. The prepared prednisolone tablet formulations arelisted in Table 4.

TABLE 3 Liquisolid tablet formulations of hydrocortisone (HSN 5 & 10mg). Liquisolid Formulations (quantity/tablet in grams) FormulationHSN-1 HSN-2 HSN-3 HSN-4 Ingredients (5 mg) (10 mg) (10 mg) (10 mg) Drugsolution 3.33% w/w 0.150 g — — — (hydrocortisone propylene glycol) Drugsolution 6.67% w/w — 0.150 g — — (hydrocortisone propylene glycol) Drugsolution 10% w/w — — 0.100 g 0.100 g (hydrocortisone propylene glycol)Avicel PH 102 (granular MCC) — — — 0.397 g Avicel PH 200 (coarse grainMCC) — 0.530 g 0.357 g — E.G.C. (granules are cellulose) 0.477 g — — —Cab-O-Sil M5 (silica mm-sized) 0.048 g 0.053 g 0.036 g 0.020 g Explotab0.092 g 0.100 g 0.067 g 0.071 g (medium starch glycolate) Tablet Weight(grams) 0.767 g 0.833 g 0.560 g 0.588 g

TABLE 4 Liquisolid tablet formulations of prednisolone (PLN 5mg).Liquisolid Formulations (quantity/tablet in grams) Formulation PLN-1PLN-2 PLN-3 PLN-4 Ingredients (5 mg) (5 mg) (5 mg) (5 mg) Drug solution4.63% w/w 0.108 g 0.108 g 0.108 g 0.108 g (prednisolone in propyleneglycol) (0.104 g for 5 mg PLN/tablet) Avicel PH 102 (granular MCC) 0.423g — — — Avicel PH 200 (coarse grain MCC) — 0.363 g 0.334 g — E.G.C.(granules are cellulose) — — — 0.306 g Cab-O-Sil M5 (silica mm-sized)0.024 g 0.045 g — 0.044 g Syloid 244 FP (silica micron-sized) — — 0.048g — Explotab 0.076 g 0.070 g 0.067 g 0.063 g (medium starch glycolate)Tablet Weight (grams) 0.631 g 0.586 g 0.557 g 0.521 g

Prednisone 1 and 5 mg Liquisolid Tablets (PSN)

Two liquisolid tablet formulations of prednisone possessing differentstrengths, i.e., 1 mg and 5 mg of prednisone per tablet, denoted asPSN-1 and PSN-2, were prepared. Both systems consisted of a mixture ofAvicel® PH 200:Cab-O-Sil® M5 at an excipient ratio equal to 10, anddifferent amounts (per tablet) of the same prednisone solution in PGpossessing a standard 5% w/w drug concentration. Specifically, eachPSN-1 tablet contained 1 mg of prednisone in the form of 0.02 g of its5% w/w drug solution, whereas PSN-2 tablets contained 5 mg of drug inthe form of 0.1 g of its 5% w/w drug solution in PG. In both liquisolidcompacts a 12% w/w of Explotab® was included. The prepared prednisoneformulations are listed in Table 5.

Spironolactone 10 mg Liquisolid Tablets (SPN)

One liquisolid tablet formulation of spironolactone, denoted as SPN-1,was prepared. The system contained 10 mg of spironolactone (per tablet)in the form of 0.1 g of its 10% w/w solution in PEG 400, and a powdersystem of Avicel® PH 102:Cab-O-Sil® M5 possessing an excipient ratioequal to 20. A 12% w/w of Explotab® was also included. The preparedspironolactone liquisolid formulation is listed in Table 5.

Hydrochlorothiazide 25 mg Liquisolid Tablets (HTZ)

One liquisolid tablet formulation of hydrochlorothiazide, namely, HTZ-1,was prepared. The system contained 25 mg of hydrochlorothiazide (pertablet) in the form of 0.1 g of its 25% w/w solution in PEG 400, and apowder system of Avicel® PH 200:Cab-O-Sil® M5 possessing an excipientratio equal to 10. A 12% w/w of Explotab® was also included. preparedHTZ-1 formulation is listed in Table 5.

TABLE 5 Liquisolid tablet formulations of prednisone (PSN 1 & 5 mg),spironolactone (SPN 10 mg) and hydrochlorothiazide (HTZ 25 mg).Liquisolid Formulations (quantity/tablet in grams) Formulation PSN-1PSN-2 SPN-1 HTZ-1 Ingredients (1 mg) (5 mg) (10 mg) (25 mg) Prednisonesolution 5% w/w 0.020 g 0.100 g — — (in propylene glycol) Spironolactonesolution 10% — — 0.100 g — 10% w/w (in polyethylene glycol MCC)Hydrochlorothiazide solution — — — 0.100 g 25% w/w (in polyethyleneglycol MCC) Avicel PH 102 (granular MCC) — — 0.595 g — Avicel PH 200(coarse grain MCC) 0.071 g 0.357 g — 0.379 g E.G.C. (granules arecellulose) 0.007 g 0.036 g 0.030 g 0.038 g Cab-O-Sil M5 (silicamm-sized) 0.022 g 0.067 g 0.099 g 0.071 g Explotab (medium starchglycolate) 0.183 g 0.560 g 0.824 g 0.580 g Tablet Weight (grams)

TABLE 6 Liquisolid tablet formulations of methyclothiazide (MTZ 5 mg)and clofibrate (CLF 50 & 100 mg). Liquisolid Formulations(quantity/tablet in grams) Formulation MTZ-1 MTZ-2 CLF-1 CLF-2Ingredients (5 mg) (5 mg) (100 mg) (50 mg) Methyclothiazide solution0.100 g 0.100 g — — 5% w/w (in polyethylene glycol MCC) Clofibrate (oilyliquid drug) — — 0.100 g 0.050 g Avicel PH 102 (granular MCC) — 0.595 g— 0.595 g Avicel PH 200 0.379 g — 0.505 g — (coarse grain MCC) Cab-O-SilM5 (silica mm-sized) 0.038 g 0.030 g 0.051 g 0.030 g Explotab 0.071 g0.099 g 0.035 g 0.035 g (medium starch glycolate) Tablet Weight (grams)0.588 g 0.624 g 0.691 g 0.710 g

Methyclothiazide 5 mg Liquisolid Tablets (MTZ)

Two liquisolid tablet formulations of methyclothiazide, denoted as MTZ-1and MTZ-2, were prepared. Both systems contained 5 mg ofmethyclothiazide (per tablet) in the form of 0.1 g of its 5% w/w drugsolution in PEG 400, and different carrier:coating systems.Specifically, the powder systems Avicel® PH 200:Cab-O-Sil® M5 (at R=10)and Avicel® PH 102:Cab-O-Sil® M5 (at R=20) were included in formulationsMTZ-1 and MTZ-2, respectively. A 12% w/w of the disintegrant Explotab®was included in both liquisolid compacts. The prepared methyclothiazidetablet formulations are listed in Table 6.

Clofibrate 50 and 100 mg Liquisolid Tablets (CLF)

Two liquisolid tablet formulations of clofibrate, denoted as CLF-1 andCLF-2, were prepared. Formulation CLF-1 contained 100 mg of this oilyliquid drug (per tablet) mixed with an Avicel® PH 200:Cab-O-Sil® M5system possessing an excipient ratio equal to 10. On the other hand,formulation CLF-2 consisted of 50 mg clofibrate (per tablet) blendedwith an Avicel® PH 102:Cab-O-Sil® M5 combination possessing an excipientratio equal to 20. A 5% w/w of the disintegrant Explotab® was includedin both liquisolid compacts. The prepared clofibrate tablet formulationsare listed in Table 6.

Gemfibrozil 60 mg Lquisold Tablets (GFZ)

An optimized liquisolid tablet formulation of gemfibrozil, denoted asGF2, was prepared. It contained 60 mg of this practicallywater-insoluble drug (per tablet) in the form of 0.1 g of its 60% w/wsuspension in polysorbate 80, mixed with an Avicel® PH 200:Cab-O-Sil®M5system possessing an excipient ratio equal to 20 in the form of 0.1 g ofits 60% w/w suspension in polysorbate 80. A 5% w/w of the disintegrantExplotab was included in the formulation which is listed in Table 7.

Nifedipine 10 mg immediate-Release Liquisolid Tablets (NFD-RR)

An optimized immediate-release liquisolid tablet formulation ofNifedipine, denoted as NFD-RR was prepared. It contained 5 mg of thispractically insoluble drug (per tablet) in the form of 0.1 g of its 5%w/w solution in polyethylene glycol 400, mixed with an Avicel® PH200:Cab-O-Sil® M5 system possessing an excipient ratio equal to 20. A 5%w/w of the disintegrant Explotab was included in the formulation whichis listed in Table 7.

Nifedipine 30 mg Sustained Release Liquisolid Tablets (NFD-SR)

An optimized immediate-release liquisolid tablet formulation ofNifedipine, denoted as NFD-SR was prepared. It contained 30 mg ofnifedipine in the form of 0.1 g of its 30% w/w suspension in PEG 400,mixed with an Avicel® PH 200:Cab-O-Sil® M5 system possessing anexcipient ratio equal to 20. Twenty-two percent (22%) of the(matrix-producing) binder hydroxypropylmethyl cellullose (HPMC) and 5%of the lubricant magnesium stearate were included in the finishedformulation which is listed in Table 7.

TABLE 7 Liquisolid tablet formulations of immediate release gemfibrozil(GFZ 60 mg) and nifedipine rapid release (NFD-RR 5 mg) and sustainedreleased (NFD-SR 30 mg). Liquisolid Formulations (quantity/tablet ingrams) Formulation GFZ NFD-RR NFD-SR Ingredients (60 mg) (5 mg) (30 mg)Gemfibrozil suspension 0.100 g — — 60% w/w (in polysorbate 80)Nifedipine solution 5% w/w — 0.100 g — (in polyethylene glycol 400)Nifedipine suspension — — 0.100 g 30% w/w (in polyethylene glycol 400)Avicel PH 200 0.500 g 0.392 g 0.392 g (coarse gran. MCC) Cab-O-Sil M50.025 g 0.020 g 0.020 g (silica mm-sized) Explotab 0.033 g 0.028 g —(sodium starch glycolate) HPMC — — 0.154 g(hydroxypropylmethylcellulose) Magnesium Stearate (lubricant) — — 0.034g Tablet Weight (grams) 0.658 g 0.540 g 0.700 g

C. Dissolution Studies

An in-vitro release study of drugs from prepared liquisolid tablets andcommercial products was performed using the USP/NF specifications (11)relevant to each drug preparation. Dissolution studies were conductedusing a standard USP/NF VanderKamp dissolution apparatus (Van-KelIndustries, Inc., Chatham, N.J.) interfaced with a Beckman DU-37automated dissolution testing spectrophotometer (Beckman InstrumentsInc., Fullerton, Calif.). The various conditions employed duringdissolution studies of products containing a particular drug, such asdissolution apparatus, rotational speed of the paddle or basket, typeand volume of dissolution medium per vessel, spectrophotometricwavelength for drug analysis, etc., are listed in Table 8.

TABLE 8 List of various conditions emplyed during dissolution studies ofliquisolid tablets and commercial products of several medications. Tradenames, strengths and manufacturers of the tested marketed products arealso included. Dissolution Condition Rotational Dissolution Maximum Drugcontent of Apparatus Speed Medium Wavelength tested products (Method)(RPM) (ml/vessel) (nm, UV range) Commercial Products ComparedHYDROCORTISONE USP/NF II 50 rpm Distilled Water 247 nm Hydrocortone 10mg Tablets (paddle)  (900 ml) (Merck Sharp & Dohme) PREDNISOLONE USP/NFII 50 rpm Distilled Water 245 nm Prednisolone 5 mg Tablets (paddle  (900ml) (Rugby Laboratories) PREDNISONE USP/NF II 50 rpm Distilled Water 241nm Meticorten 1 mg (Schering) & (paddle)  (500 ml) Deltasone 5 mgTablets (Upjohn) SPIRONOLACTONE USP/NF II 75 rpm 0.1 NHCl + 241 nmAldactone 25 mg Tablets (paddle) 0.1% w/w SLS (Searle & Co.) (1000 ml)HYDROCHLOROTHIAZIDE USP/NF I  100 rpm  0.1 NHCl 270 nm Esidrix 25 mgTablets (basket)  (900 ml) (Ciba-Geigy) METHYCLOTHIAZIDE USP/NF II 50rpm 0.1 N HCl 268 nm Methyclothiazide 5 mg Tablets (paddle) (900 ml)(Geneva Generics). CLOFIBRATE USP/NF II 75 rpm 0.5% w/w 273 nm Atromid-S500 mg Clofibrate (paddle) Tween 80 Soft Gelatia Capsules (Ayers) (1000ml)

Six individual tablets or capsules from each product were tested. In allstudies, the temperature of the dissolving medium was maintained at37±0.5° C. Dissolution samples were automatically withdrawn at regularintervals using a Rabbit peristaltic pump (Rainin Instrument Co., Inc.,Woburn, Mass.), prefiltered, filtered through a 0.45 μm nylon membrane,and analyzed spectrophotometrically (Table 8). After their assay, thedissolution samples were recirculated to their original vessels.

The spectrophotometric readings were converted into cumulative percentof drug released using the internal computation system of the BeckmanDU-37 software, which was previously fed with the following parameters:(a) absorbance reading of a standard drug solution; (b) selectedconcentration of the standard drug solution measured; and (c) maximumconcentration of the drug in the dissolution medium expected at the 100%release level. In preliminary studies, it was established thatspectrophotometric quantitation was feasible since all drugs obeyedBeer's Law at the selected wavelengths and concentration ranges.

Finally, to ensure similar sink conditions during the dissolutionprocess of prepared clofibrate liquisolid tablets, and since CLF-250 mgtablets contained only one-half the amount of clofibrate included inCLF-1100 mg tablets, the dissolution studies of the CLF-2 tabletformulation were conducted by placing 2 tablets in each vessel. For thesame reason, since CLF-1 liquisolid tablets contain 100 mg of clofibratewhich is 1/5 of the amount found in the commercial soft gelatin capsuleproduct (Atromid-S®—500 mg of clofibrate), the dissolution studies ofthe CLF-1 formulation were repeated by placing 5 clofibrate liquisolidtablets in each vessel. Results are included in FIG. 4.

D. Aging Studies

In an effort to obtain some idea on the stability of the liquisolidsystems, the effects of aging on the dissolution profile and crushingstrength of prepared hydrocortisone liquisolid tablets wereinvestigated. Specifically, HSN-3 and HSN4 formulations were compressedusing identical equipment, tooling and conditions, into 24 cylindricaltablets (each) possessing a diameter equal to 15/32″. Standardcompression forces equal to 3,600 and 3,800 lbs were employed to produceHSN-3 and HSN4 tablets, respectively. Moreover, similar compression rate(300 lbs/sec) and dwell time (1 sec) were used in all compactions.Twelve tablets from each formulation were stored under room conditions,and after 10 months their dissolution profiles and crushing strengthswere determined using equipment and conditions similar to thosepreviously employed to evaluate the fresh tablets. A comparison of thedissolution profile and tablet hardness values, obtained as an averageof six determinations from fresh and aged hydrocortisone 10 mgliquisolid tablets, is presented in Table 9 and dissolution profilesplotted in FIG. 5.

TABLE 9 Comparison of dissolution profile and crushing strength of freshand aged (10 months) hydrocortisone 10 mg liquisolid tablets (HSN-3 andHSN-4). CUMULATIVE PERCENT DRUG RELEASED^(a) TIME HSN-3 HSN-3 HSN-4HSN-4 (minutes) FRESH AGED FRESH AGED  5 68.7% 71.2% 89.5% 61.5% (4.4)(2.3) (2.7) (2.3) 10 97.6% 95.1% 98.2% 94.7% (2.1) (1.5) (2.4) (1.6) 1599.4% 97.3% 100.1% 97.6% (2.5) (1.2) (2.1) (1.0) 20 100.2% 98.7% 101.2%98.7% (1.9) (1.4) (1.2) (0.9) 30 101.3% 100.2% 102.1% 99.8% (1.2) (0.4)(0.4) (0.5) CRUSHING^(a) 8.23 kg 7.54 kg 8.75 kg 8.29 kg STRENGTH (0.36)(0.52) (0.26) (0.35) (Tablet hardness in kg) ^(a)Average of sixdeterminations. Standard deviation given parenthesis.

E. Evaluation of the Proposed Mathematical Model

The capability of the proposed formulation and mathematical model toproduce acceptably flowing and compressible liquisolid compacts wastested by assessing the flow and compression properties of severalsystems. New liquisolid formulations of hydrocortisone, methyclothiazideand clofibrate were prepared as described for the liquisolid tablets,but without the addition of a disintegrant.

Four liquisolid compacts, denoted as LC#1, LC#2, LC#3 and LC#4,containing 0.1 g (per compact unit) of a 10% w/w hydrocortisone solutionin PG mixed with different carrier:coating combinations possessingminimum excipient ratios, were prepared. Specifically, Avicel® PH102:Cab-O-Sil® M5 (R_(min)=18), Avicel® PH 200:Cab-O-Sil® M5(R_(min)=8), Avicel® PH 200: Syloid® 244 FP (R_(min)=7) and E.G.C.:Cab-O-Sil® M5 (R_(min)=7) were used as the powder systems offormulations LC#1, LC#2, LC#3 and LC#4, respectively.

Furthermore, two liquisolid compacts, denoted as LC#5 and LC#6,containing 0.1 g (per compact unit) of a 5% w/w methyclothiazidesolution in PEG 400 were prepared. The powder systems Avicel® PH102:Cab-O-Sil® M5 (R_(min)=18) and Avicel® PH 200:Cab-O-Sil® M5(R_(min)=8) possessing minimum excipient ratios were used to formulateLC#5 and LC#6, respectively. Finally, two more liquisolid compacts,denoted as LC#7 and LC#8, containing 50 and 100 mg (per compact unit) ofclofibrate, respectively, were also prepared. The powder systems Aviecl®PH 102:Cab-O-Sil® M5 (R_(min)=18) and Aviecl® PH 200:Cab-O-Sil® M5(R_(min)=8), were included at minimum excipient ratios in formulationsLC#7 and LC#8, respectively.

The flowability and compressibility of the above liquisolid compactswere assessed by means of the flow rate and pactisity measurements whichare described below. The prepared formulations along with their flowrate and pactisity determinations are presented in Tables 10 and 11.

TABLE 10 Flowability and compressibility evaluation of liquisolidcompacts containing a solution of hydrocortisone in proplylene glycol(10% w/w) Liquisolid Systems (quantity (g)/compact unit) LC #1 LC #2 LC#3 LC #4 Ingredients (HSN/PG) (HSN/PG) (HSN/PG) (HSN/PG) Hydrocortisonesolution 0.100 g 0.100 g 0.100 g 0.100 g in propylene glycol (10% w/w)Avicel PH 102 0.392 g — — — (granular MCC) Avicel PH 200 — 0.336 g 0.311g — (coarse grain MCC) E.G.C. — — — 0.283 g (granular methylcellulose)Cab-O-Sil M5 0.022 g 0.042 g — 0.041 g (silica mm-sized) Syloid 244 FP —— 0.044 g — (silica micron-sized) Compact Unit Weight (g) 0.514 g 0.478g 0.455 g 0.424 g Flow Rate (g/sec)^(a)   3.9 g/sec  10.8 g/sec  10.3g/sec  9.2 g/sec (0.7) (0.6) (0.5) (0.7) Pactisity (kg/g)^(b) 22.1 kg/g20.7 kg/g 21.4 kg/g 19.6 kg/g (1.2) (1.1) (1.4) (1.1) ^(a)Average of 8determinations. Standard deviating given in parenthesis. See text forflow rate determinations using the RRF method. ^(b)Average of 6determinations. Standard deviating given in parenthesis. See text forpactisity determinations using the LSC test.

TABLE 11 Flowability and compressibility evaluation of liquisolidcompacts containing a solution of methyclothiazide in polyethyleneglycol 400 (5% w/w) or clofibrate (oily liquid drug). Liquisolid Systems(quantity (g)/compact unit) LC #5 LC #6 LC #7 LC #8 Ingredients (MTZ/)(MTZ/) (Clofibrate) (Clofibrate) Methyclothiazide solution in 0.100 g0.100 g — — polyethlene glycol 400 (5% w/w) Clofibrate (oily liquiddrug) — — 0.050 g 0.100 g Avicel PH 102 (granular MCC) 0.537 g — 0.536 g— Avicel PH 200 (coarse grain MCC) — 0.311 g — 0.408 g Cab-O-Sil M5(silica mm-sized) 0.030 g 0.039 g 0.030 g 0.051 g Compact Unit Weight(g) 0.667 g 0.450 g 0.616 g 0.559 g Flow Rate (g/sec)^(a)   6.7 g/sec 9.2 g/sec  5.1 g/sec  5.4 g/sec (0.6) (0.4) (0.6) (0.3) Pactisity(kg/g)^(b) 30.7 kg/g 21.3 kg/g 37.2 kg/g 24.9 kg/g (1.1) (1.4) (2.1)(1.6) ^(a)Average of 8 determinations. Standard deviating given inparenthesis. See text for flow rate determinations using the RRF method.^(b)Average of 6 determinations. Standard deviating given inparenthesis. See text for pactisity determinations using the LSC test.

Flowability Evaluation

The flow rate and consistency of the prepared liquisolid systems werecharacterized using a recording powder flowmeter (RPF) assembly.Experimental conditions for flow rate determinations using the RPF weresimilar to those employed during the liquisolid flowability (LSF) test.Furthermore, the conditions characterizing a liquisolid system asacceptably flowing were similar to those set during LSF testing andΦ-value determinations. Consequently, a liquid/powder admixture wasconsidered acceptably flowable if 30 grams of the mixture were able topass through the hopper of the RPF assembly (at a vibration levelproduced by a standard pressure of 10 psi) exhibiting a flow rate of notless than 4 grams/sec and flow consistency without any blockages at thestart or during the powder flow. Flow rates of prepared liquisolidtablet formulations, representing the average of 8 determinations, aregiven in Tables 10 and 11.

Compressibility Evaluation

The prepared liquisolid systems were manually compressed intocylindrical tablets of desired weight using a model B hydraulic CarverLaboratory Press (Fred S. Carver, Inc., Hydraulic Equipment, Summit,N.J.). Round, flat-face punches and die units of diameters varying from{fraction (13/32)}″ to {fraction (15/32)}″ were used. There were noinscriptions on the tooling. Standard pactisity conditions (SPC), i.e.,plateau compression settings such as pressure of pactisity (P_(Ω)) equalto 64,650 psi/g, pactisity pressure rate (r_(Ω)) equal to 12,930 psi/gsec, and a pactisity pressure dwell time (t_(Ω)) equal to 1 sec, wereused during compression. The tabletting conditions corresponding to suchSPC, i.e., maximum tabletting compression force (F_(t)) and tablettingcompression rate (r_(t)), employed to compress a cylindrical liquisolidtablet possessing a desired weight W_(t) and a diameter D_(t)(die-diameter), were calculated using Eqs. 15 and 16.

F _(t)=(π/4)P ¹⁰⁶ D_(t) ²  (Eq. 15)

r _(t)=(π/4)r_(Ω)W_(t)D_(t) ²  (Eq. 16)

Using such SPC, six tablets from each system were compressed, and thepactisities (Ω) of the liquisolid formulations were assessed andcompared to the pactisity limit (i.e., Ω=20 kg/g) of acceptablecompressibility. Specifically, 6 tablets from each formulation werefirst weighed and their average tablet weight, W_(t), was recorded.Then, the tablets were crushed using a Schleuniger-2E tablet hardnesstester and their average crushing strength, S_(c), was assessed.Finally, the pactisity, Ω, of the liquisolid system under investigationwas calculated (in kg/g) using Eq. 17, i.e., Ω=S_(c)/W_(t). Pactisity Ωof a liquisolid compact is the crushing strength of a one-gram tablet ofthe system compressed at SPC. According to conditions defined during LSCtesting, the liquisolid system under investigation was consideredacceptably compressible if it could be compressed to a pactisity greaterthan or equal to 20 kg/g, without any visual evidence of liquid beingsqueezed out of the compacts during compression. Pactisity results ofthe prepared liquisolid compacts are included in. Tables 10 and 11.

F. In Vivo Studies in Rats

In-vivo studies were conducted for testing liquisolid tabletformulations of clofibrate, gemfibrozil and nifedipine against theircommercial counterparts. Male Sprague-Dawley rats (275-300g) fastedovernight and were assigned to groups of six animals each. All dosings,defined in FIGS. 6, 7 and 8, were orally administered. Blood sampleswere collected at specified intervals and analyzed using RP-HPLCmethods.

Results and Discussion

The measured flow rates and pactisities of the liquisolid compacts LC#1-8 are given in Tables 10 and 11. All systems prepared according tothe formulation-mathematical model of the present invention displayedacceptable flow and compression properties. Tested using the RPFassembly, all preparations exhibited flow rates higher than 4 g/sec andconsistent flow without any blockages at the start or during thepowder's passage through the hopper orifice. Moreover, the sameliquid/powder admixtures, compressed at standard pactisity conditions(SPC), yielded pactisities greater than, or close to 20 kg/g. Such flowrate and pactisity results comply with the previously set limits ofacceptable flowability and compressibility, providing verification forthe validity of the mathematical model to produce free-flowing andreadily compressible liquisolid systems.

Comparisons between the drug dissolution profiles of liquisolid tabletsand their commercial counterparts are illustrated in FIGS. 2-4. As shownthere, the prepared liquisolid tablets not only exceeded USP dissolutionrequirements but often yielded significantly higher drug release ratesthan those of their commercial counterparts.

In general, it has been observed that the drug release superiority ofliquisolid tablets is inversely proportional to the aqueous solubilityof the contained drug. Accordingly, the most impressive difference indissolution profiles was shown in the case of the liquid lipophilicclofibrate where, within the first hour of dissolution, 100% of the drugwas released from the liquisolid tablets but only 6% of the drug wasreleased from the costly commercial soft gelatin capsules.

Since drug dissolution is the rate limiting step in oral drug absorptionof nonpolar molecules, liquisolid systems might also present asubstantial in-vivo superiority over their commercial counterparts. Infact, controlled in-vivo studies using clofibrate liquisolid andcommercial products, recently conducted in rats, have confirmed thesuperior in-vitro release patterns of liquisolid compacts. As shown inFIG. 6, the extent and rate of systemic absorption of this nonpolarmolecule from liquisolid tablets were significantly greater than thosefrom the costly commercial soft gelatin capsules. Such findings mighteven permit the use of lower doses.

Furthermore, as shown in FIGS. 7 and 8, liquisolid compacts ofgemfibrozil and nifedipine displayed significantly superior drug plasmalevels in rats as compared to their highly expensive commercialcounterparts. Specifically, a 10 to 12 times higher bioavailability ofgemfibrozil in rats was observed from liquisolid compacts (GFZ, 60 mg)as compared to its commercial counterpart (LOPID 600 mg tablets). Athree to four times higher bioavailability of nifedipine in rats wasobserved from liquisolid compacts (NFD-RR, 5 mg) as compared to itscommercial counterpart (soft gelatin capsules of nifedipine). Suchfindings suggest that the bioavailability of gemfibrozil and nifedipinefrom liquisolid compacts may be significantly enhanced in humans, thatlower doses may be possible, and that more economic products could bemade.

Finally, dissolution profiles and crushing strengths of fresh and10-months old HSN-3 and HSN4 liquisolid tablets of hydrocortisone arepresented in Table 9. Although it appears that the tablet hardness ofthe systems deteriorated due to the presence of liquid, the observeddecrease in crushing strength is only about 6% to 9% of the originaltablet hardness. A comparison of the dissolution curves of fresh andaged hydrocortisone liquisolid tablets is also illustrated in FIG. 5,which shows that, except for the first five minutes, the dissolutionrates were not significantly different.

A representative sample for the potential of sustained-releaseliquisolid compacts is given in FIG. 9. As shown there, the in-vitrorelease rate of nifedipine (over a 12-hour period) fromsustained-release liquisolid tablets was more constant (zero-orderrelease) than that displayed by its highly expensive commercialcounterpart (PROCARDIA-XL).

In very recent studies, the effects of various formulation parameterssuch as excipient ratio, load factor, disintegrant level, solvent systemand drug solution concentration on the drug release of liquisolidsystems were investigated. It has been shown that these parameters mayaffect, to various extents, the dissolution characteristics ofliquisolid compacts, and thus they may be used for optimization.

In previous patents on liquisolid systems, a specific and systematicmethod which ensures the production of acceptably flowing andcompressible liquisolid compacts or acceptably flowing (with goodplugging potential) liquisolid microsystems, has been described throughthe so called liquisolid flowability and liquisolid compressibilitytesting procedures. These tests are based on the fundamental propertiesof powders termed the “flowable liquid retention potential” and thecompressible liquid retention potential”.

No where in the prior art is it shown or suggested the concept orproducing acceptably flowing and compressible powder systems, which canbe tableted or encapsulated while containing (permanently) nonvolatileliquids in their bulk.

While there are some patents related to the deposition of simethicone(oily liquid) onto water-soluble solid powders such as lactose, sucrose,mannitol and dextrates, believed to owned by Valentine, in these patentsthe production of acceptably flowing and compressible liquid-powdersystems is not claimed and actually it is impossible to be claimed sincethe solid simethicone powders of any grade are not powders, rather theyresemble a muddy liquid-powder mass.

The present invention is thus addressed to the production by a simpledirect blending procedure (the key condition) of acceptably flowing and,simultaneously, acceptably compressible or pluggable powders containingnonvolatile liquids into their bulk.

Such liquid applications powder systems are called “liquisolid system”and could be directly tableted or encapsulated. The powder substrate ofthese systems will primarily comprise of microcrystalline cellulose,starch and silica at various ratios which will ensure acceptable flowand compression characteristics. These three water-insoluble powders aremost preferable since they possess high liquid retention potentialsthereby producing small unit doses. In addition, water solublepowder-polymers such as povidone, hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose (HPC), ethyl cellulose grades, and solidpolyethylene glycols with molecular weights greater than 1,000, may bealso included in the powder substrate.

Examples of non-volatile liquids in accordance with the presentinvention include but are not limited to propylene glycol, polyethyleneglycols 200, 300 and 400, polysorbates 20 and 80 (Tween 20 and 80),glycerin, soybean oil, olive oil, light mineral oil,N,N-dimethylacetamide, etc. and equivalents thereof. Examples ofvolatile solvents in accordance with the present invention include butare not limited to alcohol, acetone, methylene chloride, water, etc. andequivalents thereof. Such volatile solvents will be evaporated duringthe manufacturing process of the present invention. However thenon-volatile solvents will be permanently embedded in the powdersubstrate of the finished product.

Based on my knowledge acquired from my formulation experience with thesesystems, depending on the consistency of the powder substrate, thequantity of solid drug dispersed in the liquid medication and thephysiochemical properties of the liquid vehicle used (polarity,hydrophilicity, viscosity, wetting ability and its affinity with thepowder substrate), the acceptable liquid-to-powder percent ratios(meaning liquid vehicle over powder substrate, not including the drugpowder) will range from 2% to 52%, the most preferable range being 10%to 35%.

Any nonvolatile liquid can be used as the liquid vehicle in suchsystems. Examples of such liquids (but not limited to) are propyleneglycol, glycerin, polyethylene glycols 200, 300 and 400, polysorbates 80and 20, lecithin, oils, liquid drugs, etc. Furthermore, the initialinclusion of some volatile liquids (e.g., water, alcohol, acetone,methylene chloride, etc.), are also a part of the process of the presentinvention. These volatile vehicles will, of course, evaporate by dryingthe liquisolid granular system. These volatile solvents are notpreferred to be used on a regular basis, but they might be needed forspecial formulation purposes. Note, however, that in such case, thedried liquisolid system will still contain the nonvolatile liquidvehicle, originally incorporated along with its volatile counterpart.

EXAMPLE #1

Let us assume that one wishes to prepare on acceptably flowing andcompressible liquisolid system of a solid drug, say hydrocortisone, inthe form of its solution in PROPYLENE GLYCOL, using microcrystallinecellulose Avicel Ph 200 (coarse granular grade) as the carrier powdermaterial and amorphous silicon dioxide Syloid 244 (micron-sized silica)as the coating (or covering) powder material.

Excluding the disintegrant and lubricant needed in the finished product,an acceptably flowing and compressible liquisolid compact with a 10-mgpotency may consist of:

HYDROCORTISONE=1-2.5%

PROPYLENE GLYCOL=10-22%

AVICEL PH 200 (MCC)=69-85%

SYLOID 244 FP (silica)=3-6.5%

Note that the above ranges represent cases in which different mixing andtabletting equipment may be used; different liquid vehicles other thanpropylene glycol may be employed to prepare the liquid medication; anddifferent flow and compression properties may be desired.

EXAMPLE 2

In the previous example, if a polymeric additive such as Povidone isadded into the initial liquid medication, the acceptably flowing andpluggable liquisolid microsystem will consist of:

HYDROCORTISONE=2-3.5%

PROPYLENE GLYCOL=20-35%

POVIDONE=3-6.5%

MICROCRYSTALLINE=38-67% CELLULOSE (Avicel Ph 200)

SILICA=8-17%

For a 10 mg Potency system

EXAMPLE 3

In the previous example, if a starch powder, say sodium starch Glycolateor starch 1500 or corn starch, is added along with the Avicel Ph 200(MIC) as the carrier powder materials, the new system may consist of:

HYDROCORTISONE=2-3.5%

PROPYLENE GLYCOL=20-35%

POVIDONE=3-6.5%

STARCH=7-16%

AVICEL PH 200 (MCC)=30-50%

SYLOID 244 FP (Silica)=9-18%

EXAMPLE 4

Let us assume that one wishes to prepare an acceptably flowing andcompressible liquisolid system of another solid drug, sayhydrochlorothiazide, in the form of its suspension in PolyethyleneGlycol 400 (Pre-400), using Avicel Ph 200 (coarse granular MCC) as thecarrier powder material and SYLOID 244 FP (silica) as the coating powdermaterial.

Excluding the disintegrant and lubricant needed in finished product, anacceptable flowing and compressible liquidsolid compact with a 50-mgpotency may consist of:

HYDROCHLOROTHIAZIDE=10-13%

PEG-400=12-23%

AVICEL PH 200 (MCC)=59-76%

SYLOID 244 TP (SILILA)=2-5%

All previous examples may be also applied using an additional volatilesolvent such as alcohol or water in combination with the nonvolatilesolvents mentioned in those examples. Also other nonvolatile solvents,other than propylene and polyethylene glycols may be used.

All appropriate liquids—powder combinations which will give acceptablyflowing and compressible systems while maintaining acceptable unitsizes, may be easily defined with the liquid load factor (L_(f)) andpowder excipient ratio (R) combinations used and described in my priorpatent applications incorporated by reference herein.

The L_(f)/R Relationship ensures the maximum amount of liquid to bemixed with the minimum amount of powder substrate in order to produceacceptably flowing and compressible systems.

Thus, the present invention includes any combination of L_(f) and Rbelow the optimum one and above a combination that will produce anunacceptable unit-dose-size.

In my previous patent applications, the combinations of L_(f) and Rwhich will produce unacceptable unit-dose-size may be convenientlypredicted using the U-_(w)-relation also described in the previouspatent application.

EXAMPLE 5

In the previous example (#4), if a polymeric additive such as povidoneis added into the initial liquid medication, the acceptably flowing andpluggable liquisolid microsystem may consist of:

HYDROCHLOROTHIAZIDE=11-16%

PEG-400=20-35%

POVIDONE=2-8%

AVICEL PH 200 (MCC)=21-57%

SYLOID 244 FP (Silica)=10-20%

For a 50-mg Potency System

EXAMPLE 6

In the previous example (#5), if a starch powder (from those describedin example #3) is added along with the Avicel PH 200 (MCC) as thecarrier powder materials, the new system may consist of:

HYDROCHLOROTHIAZIDE=11-16%

PEG-400=20-35%

POVIDONE=2-8%

STARCH=5-17%

AVICEL PH 200 (MCC)=16-40%

SYLOID 244 FP (Silica)=10-20%

The invention is not limited by the embodiments described above whichare presented as examples on out can be modified in various ways in thescope of protection defined by the appended patent claims.

REFERENCES

1. W. R. Ebert. Soft elastic gelatin capsules: unique dosage form.Pharm. Tech., 1:44-50 (1977).

2. E. Nelson. Physicochemical and pharmaceutic properties of drugs thatinfluence the results of clinical trials. Clin. Pharmacol. Ther.,3:673-681 (1962).

3. S. Spireas. Development of a New Theory for Powdered SolutionTechnology and Evaluation of Microcrystalline and Amorphous Cellulosesas Carriers for Prednisolone Powdered Solutions. Master of sciencethesis, St. John's University, Jamaica, N.Y., 1988.

4. S. Spireas, C. I. Jarowski and B. D. Rohera. Powdered SolutionTechnology: Principles and Mechanism. Pharm. Res., 9:1351-1368 (1992).

5. C. C. Liao. Physicochemical Properties of Selected Powdered DrugSolutions. Doctor of philosophy thesis, St. John's University, Jamaica,N.Y., 1983.

6. H. M. Lin. The Use of Amorphous Silicas as Carriers for a LiquidDrug, Chlorpheniramine Sustained Release Tablets. Master of sciencethesis, St. John's University, Jamaica, N.Y., 1986.

7. M. Rahman. A Physicochenical Study of Tablets Containing PowderedSolutions of Methylene Blue and Spironolactone. Master of sciencethesis, St. John's University, Jamaica, N.Y., 1988.

8. A. K. Sheth and C. I. Jarowski. Use of Powdered Solutions to Improvethe Dissolution Rate of Polythiazide Tablets. Drug Dev. Ind. Pharm.,16:769-777 (1990).

9. S. Spireas. Theoretical and Practical Aspects of “LiquisolidCompacts”. Doctoral dissertation, St. John's University, Jamaica, N.Y.,1993 (to be published).

10. Remington's Pharmaceutical Sciences, Seventeenth Edition, MackPublishing Company, Easton, Pa., 1985.

11. The United States Pharmacopeia XXII, United States PharmacopeialConvention, Inc., Rockville, Md., 1990.

I claim:
 1. A method of producing a free flowing and compressibleliquid/powder admixture of an active drug substance, which methodcomprises converting the active drug substance into a liquisolid system,comprising the steps of: (a) dissolving or otherwise introducing saiddrug substance into a non-volatile liquid or a mixture of non-volatileand volatile liquids, to form a liquid mixture; (b) selecting at leastone powder substrate; (c) admixing the liquid mixture of paragraph (a)and the powder substrate of paragraph (b) to produce a non-adherentfree-flowing and compressible liquid/powder mass admixture, the amountsof drug substance and powder substrate being selected to optimize flowand compressibility and wherein the liquid-to-powder substrate ratioranges from 2% to 52%.
 2. The method of claim 1 including the step ofapplying a solid coating powder material to discrete amounts of saidliquid/solid powder mass admixture.
 3. The method of claim 1 wherein theliquid mixture of paragraph(a) comprises a solid water-insoluble drug ina first solvent and optionally a second solvent, and the drug substanceis a solid or liquid non-volatile lipophilic medication.
 4. The methodof claim 1 comprising the step of mixing the liquid/powder massadmixture with an amount of lubricant effective for tableting orencapsulating the liquid/powder admixture.
 5. The method of claim 3further comprising the step of adding to the liquid/powder massadmixture an amount of disintegrant effective to produce liquisolidcompacts possessing rapid drug release properties.
 6. The method ofclaim 3 further comprising the step of adding to the liquid/powder massadmixture an amount of binder effective to produce liquisolid compactspossessing sustained drug release properties.
 7. The method of claim 1wherein the drug substance is a liquid medication selected from thegroup consisting of a drug solution, a drug suspension and a liquiddrug.
 8. The method of claim 7 wherein said liquid is a non-volatilesolvent or a combination of several non-volatile solvents or acombination of non-volatile and volatile solvents.
 9. The method ofclaim 7 wherein the drug solution and drug suspension each comprises asolid water-insoluble drug substance in a first solvent and optionally asecond solvent, and the liquid drug substance is a liquid-non-volatilelipophilic medication.
 10. The method of claim 1 wherein thenon-volatile liquids are selected from the group consisting of liquidpolysorbates, other liquid surface active agents, liquid polyethyleneglycols, proplylene glycol, glycerin, dimethylacetimide,dimethylformide, pharmasolve and oils.
 11. The method of claim 1 whereinthe volatile liquids are selected from the group consisting of alcohol,water, acetone, methylene chloride and methanol.
 12. The method of claim10 wherein the non-volatile liquids are present in the final liquisolidsystem in quantities ranging from 0.1% w/w to 35% w/w.
 13. The method ofclaim 11 wherein the initial quantities of the volatile liquids beforedrying range from 1% w/w to 50% w/w of the final liquisolid system andthe quantities of the volatile liquids remaining in the final liquisolidsystem after drying do not exceed 5% w/w.
 14. The method of claim 3wherein liquisolid compacts are produced which are tablets or capsules.15. The method of claim 4 wherein liquisolid compacts are produced whichare tablets or capsules.
 16. The method of claim 1 wherein the carriermaterial comprises a porous material possessing sufficient absorptionproperties to permit absorption of the liquid mixture into the carriermaterial.
 17. The method of claim 1 wherein the carrier material isselected from the group consisting of microcrystalline and amorphouscelluloses, cellulose derivatives hpmc, hpc and other, polyvinylpyrrolidone, cyclodextrins, starches and mixtures thereof.
 18. Themethod of claim 2 wherein the coating material comprises a materialhaving a particle size in the range of about ten nm to five thousand nmand possessing sufficient absorptive properties to permit absorption ofthe coating material onto a wet mixture thereby converting the wetmixture into a non-adherent, flowable and compressible liquid/powdermixture.
 19. The method of claim 2 wherein the coating material is anamorphous silicon dioxide.
 20. A free-flowing and readily compressibleliquid/power admixture produced by converting a liquid medication whichis a drug solution, a drug suspension or a liquid drug, into aliquisolid system, said converting comprising the steps of:
 1. selectinga weight of the liquid medication to be included in a single liquisolidcompact;
 2. selecting a weight of a carrier material to be included inthe liquisolid system, said carrier material being the powder substrateof the liquisolid system;
 3. admixing the liquid medication with thepowder substrate to produce a wet mixture; and
 4. blending the wetmixture with a coating material to produce a dry-looking, nonadherent,free-flowing and compressible liquid powder admixture and wherein theliquid-to-powder substrate ratio ranges from 2% to 52%.
 21. Theliquid/powder admixture of claim 20, further comprising an amount oflubricant effective for tableting or encapsulating the liquid/powderadmixture.
 22. The liquid/powder admixture of claim 21, furthercomprising an amount of disintegrant effective to produce liquisolidcompacts possessing immediate release properties.
 23. The liquid/powderadmixture of claim 21, further comprising an amount of binder effectiveto produce liquisolid compacts possessing sustained drug releaseproperties.
 24. The liquid/powder admixture of claim 21, wherein theliquid medication is a drug solution or a drug suspension.
 25. Theliquid/powder admixture of claim 20, wherein the drug solution and drugsuspension each comprises a solid water-insoluble drug in a solvent andthe liquid drug is a liquid lipophilic medication.
 26. The liquid/powderadmixture of claim 25 wherein the liquisolid compacts are tablets orcapsules.
 27. The liquid/powder admixture of claim 20, wherein thecarrier material comprises a porous material possessing sufficientabsorption properties to permit absorption of the liquid medication intothe carrier material.
 28. The liquid/power admixture of claim 21,wherein the carrier material is selected from the group consisting ofmicrocrystalline cellulose, amorphous cellulose, and mixtures thereofstarches.
 29. The liquid/powder admixture of claim 21, wherein thecoating material comprises a material having a particle size of about 10nm to 5,000 nm and possessing sufficient absorptive properties to permitadsorption of the coating material onto the wet mixture, therebyconverting the wet mixture into non-adherent, flowable and compressibleliquid/powder admixture.
 30. The liquid/powder admixture of claim 21,wherein the coating material is an amorphous silicon dioxide.
 31. Theliquid/powder admixture of claim 21, wherein the liquid medication is adrug solution or a liquid drug.
 32. The liquid/powder admixture of claim21 wherein the drug solution and drug suspension each comprises a solidwater-insoluble drug in a solvent and the liquid drug is a liquidlipophilic medication.
 33. The admixture of claim 32 wherein the solventis a non-volatile solvent or a combination of several non-volatilesolvents or a combination of non-volatile and volatile solvents.
 34. Theadmixture of claim 33 wherein the non-volatile solvents are selectedfrom the group consisting of liquid polysorbates, liquid polyethyleneglycols, propylene glycol, glycerine, dimethylacetimide, pharmasolve andoils.
 35. The admixture of claim 33 wherein the volatile solvents areselected from the group consisting of alcohol, water, acetone, methylenechloride and methanol.
 36. The admixture of claim 34 wherein thenon-volatile solvents are present in the final liquisolid system inquantities ranging from 0.1% w/w to 35% w/w.
 37. The admixture of claim33 wherein the initial quantities of the volatile solvents before dryingrange from 1% w/w to 50% of the final liquisolid system and thequantities of the volatile solvents remaining in the final liquisolidsystem after drying do no exceed 5% w/w.
 38. The liquid/powder admixtureof claim 23, wherein the liquisolid compacts are tablets or capsules.39. The liquid/powder admixture of claim 21, wherein the carriermaterial comprises a porous material possessing sufficient absorptionproperties to permit absorption of the liquid medication into thecarrier material.
 40. The method of claim 1 wherein the liquid-to-powdersubstrate ratio ranges from 10% to 35%.
 41. The admixture of claim 20wherein the liquid-to-powder substrate ratio ranges from 10% to 35%.